Sustained protein synthesis and reduced eEF2K levels in TAp73^-\- mice brain: a possible compensatory mechanism

Abstract

The transcription factor p73 is a member of the p53 family, of which the transactivation domain containing isoform (TAp73) plays key roles in brain development and neuronal stem cells. TAp73 also facilitates homoeostasis and prevents oxidative damage in vivo by inducing the expression of its target genes. Recently, we found that in addition to its role in regulation of transcription, TAp73 also affects mRNA translation. In cultured cells, acute TAp73 depletion activates eEF2K, which phosphorylates eEF2 reducing mRNA translation elongation. As a consequence, there is a reduction in global proteins synthesis rates and reprogramming of the translatome, leading to a selective decrease in the translation of rRNA processing factors. Given the dramatic effects of Tap73 depletion in vitro it was important to determine whether similar effects were observed in vivo. Here, we report the surprising finding that in brains of TAp73 KO mice there is a reduced level of eEF2K, which allows protein synthesis rates to be maintained suggesting a compensation model. These data provide new insights to the role of TAp73 in translation regulation and the eEF2K pathway in the brain.

Skin immunity and its dysregulation in psoriasis

“…While skin development and homeostasis are regulated by p63 [11][12][13], like in other organs, apoptosis [2,14] is mainly regulated by protective proteins such as p53 [15][16][17][18], and its family members [19,20], powerful transcription factors [21,22] which regulation [23][24][25][26] protects from the development of tumors [27][28][29][30]. So far, there is no evidence in the skin of the third member of the p53/ p63/p73 family, p73 itself [31][32][33][34][35][36][37][38]. A second major regulator of cell death is in fact the pro-survival BCL-2 protein family (BCL-2, BCL-XL, MCL-1, BCL-W and A1/BFL1) [27,[39][40][41], counterbalanced by the BH3only proteins (BAX and BAK) [31,42] causing the depolarization of the mitochondrial outer membrane permeabilization (MOMP) [43] and caspasedependent death [44][45][46][47].…”

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

“…During the past decade, a few reports have shed light on the connections between the ribosomal biogenesis and other members of the p53 family. For example, two papers have recently unveiled a role for TAp73 in controlling the translation of mRNAs encoding nucleolar proteins, thus in turn affecting rRNA processing and global protein synthesis [78,79] (Fig. 2).…”

“…Acute downregulation or chemical inhibition of TAp73 impairs the translation of nucleolar protein, which reduces the rRNA processing and the polysomal/subpolysomal ratio, ultimately leading to an impaired global protein synthesis [78]. In TAp73 −/− mice, a compensatory mechanism occurs that allows the maintenance of global protein synthesis by bypassing the checkpoint set up by the translational elongation factor eEF2K [79].…”

TP73-AS1 is induced by YY1 during TMZ treatment and highly expressed in the aging brain

“…Long noncoding RNA (lncRNA) are regulatory RNA molecules known to play important roles in cancer such as promoting resistance to therapy [12,13]. The lncRNA TP73-AS1 is a gene neighbor of the transcription factor (TF) p73, a member of the p53 TF family [14] known to play important roles in aging [15][16][17], cancer [18][19][20][21][22][23] and brain development [24][25][26][27] by regulating gene expression at the transcriptional and translational levels [28,29]. LncRNA function by diverse mechanisms including by regulating gene expression in cis [30] however, TP73-AS1 does not regulate p73 in GBM stem cells [31] and to best of our knowledge was not found to regulate p73 in other biological scenarios.…”